IRE1α is an endogenous substrate of endoplasmic-reticulum-associated degradation.


Journal Article

Endoplasmic reticulum (ER)-associated degradation (ERAD) represents a principle quality control mechanism to clear misfolded proteins in the ER; however, its physiological significance and the nature of endogenous ERAD substrates remain largely unexplored. Here we discover that IRE1α, the sensor of the unfolded protein response (UPR), is a bona fide substrate of the Sel1L-Hrd1 ERAD complex. ERAD-mediated IRE1α degradation occurs under basal conditions in a BiP-dependent manner, requires both the intramembrane hydrophilic residues of IRE1α and the lectin protein OS9, and is attenuated by ER stress. ERAD deficiency causes IRE1α protein stabilization, accumulation and mild activation both in vitro and in vivo. Although enterocyte-specific Sel1L-knockout mice (Sel1L(ΔIEC)) are viable and seem normal, they are highly susceptible to experimental colitis and inflammation-associated dysbiosis, in an IRE1α-dependent but CHOP-independent manner. Hence, Sel1L-Hrd1 ERAD serves a distinct, essential function in restraint of IRE1α signalling in vivo by managing its protein turnover.

Full Text

Duke Authors

Cited Authors

  • Sun, S; Shi, G; Sha, H; Ji, Y; Han, X; Shu, X; Ma, H; Inoue, T; Gao, B; Kim, H; Bu, P; Guber, RD; Shen, X; Lee, A-H; Iwawaki, T; Paton, AW; Paton, JC; Fang, D; Tsai, B; Yates, JR; Wu, H; Kersten, S; Long, Q; Duhamel, GE; Simpson, KW; Qi, L

Published Date

  • December 2015

Published In

Volume / Issue

  • 17 / 12

Start / End Page

  • 1546 - 1555

PubMed ID

  • 26551274

Pubmed Central ID

  • 26551274

Electronic International Standard Serial Number (EISSN)

  • 1476-4679

International Standard Serial Number (ISSN)

  • 1465-7392

Digital Object Identifier (DOI)

  • 10.1038/ncb3266


  • eng